U.S. patent number 4,546,152 [Application Number 06/587,332] was granted by the patent office on 1985-10-08 for poly(p-dioxanone) polymers having improved radiation resistance.
This patent grant is currently assigned to Ethicon, Inc.. Invention is credited to Rao S. Bezwada, Dennis D. Jamiolkowski, Donald F. Koelmel, Shalaby W. Shalaby.
United States Patent |
4,546,152 |
Koelmel , et al. |
October 8, 1985 |
Poly(p-dioxanone) polymers having improved radiation resistance
Abstract
An absorbable, radiation sterilizable, normally solid polymer
comprising a copolyester that comprises repeating divalent units of
the formulas: (A) --O--CO--CH.sub.2 --O--CH.sub.2 CH.sub.2 --, and
(B) --G--, and (C) --O--CO--CHR--O--.sub.m Ph--O--CHR--CO--O--
wherein G represents the residue after removal of the hydroxyl
groups of a dihydric alcohol, wherein Ph represents 1,2-, 1,3-, or
1,4-phenylene or alkyl- or alkoxy-substituted phenylene, wherein m
represents a number having a value of 0 or 1, wherein R represents
hydrogen or lower alkyl, and wherein the divalent units (A), (B),
and (C) are bonded to each other through ester groups contained in
said units.
Inventors: |
Koelmel; Donald F. (Lebanon,
NJ), Jamiolkowski; Dennis D. (Long Valley, NJ), Shalaby;
Shalaby W. (Lebanon, NJ), Bezwada; Rao S. (Whitehouse
Station, NJ) |
Assignee: |
Ethicon, Inc. (Somerville,
NJ)
|
Family
ID: |
24349378 |
Appl.
No.: |
06/587,332 |
Filed: |
March 7, 1984 |
Current U.S.
Class: |
525/437;
606/231 |
Current CPC
Class: |
A61L
17/105 (20130101); A61L 27/18 (20130101); C08G
63/672 (20130101); A61L 27/18 (20130101); C08L
67/00 (20130101) |
Current International
Class: |
A61L
17/00 (20060101); A61L 17/10 (20060101); A61L
27/18 (20060101); A61L 27/00 (20060101); C08G
63/00 (20060101); C08G 63/672 (20060101); C08G
063/66 () |
Field of
Search: |
;525/417,419,437,444,448
;528/173,176,193,194,195,206,207,209,295 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Lee; Lester L.
Attorney, Agent or Firm: Metz; Charles J.
Claims
What is claimed is:
1. An absorbable, radiation sterilizable, normally solid polymer
comprising a copolyester that comprises repeating divalent units of
the formulas:
(A) --O--CO--CH.sub.2 --O--CH.sub.2 CH.sub.2, and
(B) --G--, and
(C) --O--CO--CHR--O).sub.m Ph--O--CHR--CO--O--
wherein G represents the residue after removal of the hydroxyl
groups of a dihydric alcohol, wherein Ph represents 1,2-, 1,3-, or
1,4- phenylene or alkyl- or alkoxy-substituted phenylene, wherein m
represents a number having a value of 0 or 1, wherein each R
individually represents hydrogen or lower alkyl, and wherein the
divalent units (A), (B), and (C) are bonded to each other through
ester groups contained in said units, wherein said polymer is
produced by reacting p-dioxanone with a polyester comprising the
repeating divalent units (B) and (C) as defined above.
2. The polymer of claim 1 wherein Ph represents 1,4-phenylene.
3. The polymer of claim 1 wherein Ph represents 1,3-phenylene.
4. The polymer of claim 1, 2, or 3 wherein G represents
polymethylene of from 3 to 6 carbon atoms.
5. The polymer of claim 1, 2, or 3 wherein m is zero.
6. The polymer of claim 4 wherein m is zero.
7. The polymer of claim 1, 2, or 3 wherein m is one.
8. The polymer of claim 4 wherein m is one.
9. The polymer of claim 1 wherein the divalent units are of the
formula: ##STR8##
10. The polymer of claim 1 wherein the divalent units are of the
formula: ##STR9##
11. The polymer of claim 1 wherein the divalent units are of the
formula: ##STR10##
12. The polymer of claim 1 wherein the divalent units (A)
constitute from about 59 to about 99 weight percent of the
copolyester.
13. The polymer of claim 1 wherein the divalent units (A)
constitute from about 75 to about 90 weight percent of the
copolyester.
14. The polymer of claim 1, 2, 3, 9, 10, 11, 12, or 13 in the form
of a fiber.
15. The polymer of claim 4 in the form of a fiber.
16. The polymer of claim 5 in the form of a fiber.
17. The polymer of claim 6 in the form of a fiber.
18. The polymer of claim 7 in the form of a fiber.
19. The polymer of claim 8 in the form of a fiber.
Description
The invention relates to polyers made from p-dioxanone, and to the
valuable surgical products that can be made therefrom. The polymers
have enhanced radiation resistance and other valuable
attributes.
BACKGROUND OF THE INVENTION
Synthetic absorbable polymers have been used to produce various
surgical products such as sutures, implants, prostheses, and the
like, for several years. Illustrative U.S. Patents that disclose
such polymers are U.S. Pat. Nos. 3,297,033, 3,044,942, 3,371,069,
3,531,561, 3,636,956, Re. 30,170, and 4,052,988.
Implantable surgical devices must be sterile prior to implanting in
the body. Sterilization of devices is usually accomplished by the
use of heat, ethylene oxide, or gamma radiation using a .sup.60 Co
source. In many cases, the use of gamma radiation is the most
convenient and most certain way to effect sterilization. However,
all of the synthetic absorbable polymers now in commercial use are
degraded at least some extent by gamma radiation. Therefore, unless
for some reason degradation of the polymer is desired (for
instance, to accelerate the absorption rate), the use of gamma
radiation is ordinarily precluded for the purpose of sterilizing
the presently commercial synthetic absorbable polymers.
This invention provides a new class of polymers that are absorbable
and which can be sterilized by gamma radiation while still
retaining a desirable level of physical and biological
properties.
SUMMARY OF THE INVENTION
The polymers provided by the invention are derived from
p-dioxanone, and certain moieties that impart enhanced resistance
to degradation by gamma radiation. The polymers of the invention
are copolyesters that comprise repeating divalent units of the
formulas:
(A) --O--CO--CH.sub.2 --O--CH.sub.2 --CH.sub.2 --, and
(B) --G--, and
(C) --O--CO--(CHR--O--).sub.m --Ph--O--CHR--CO--O--
wherein G represents the residue after removal of the hydroxyl
groups of a dihydric alcohol, wherein Ph represents phenylene or
alkyl- or alkoxy-substituted phenylene, and wherein m represents a
number having a value of 0 or 1, wherein each R individually
represents hydrogen or lower alkyl, and wherein the divalent units
(A), (B), and (C) are bonded to each other through ester groups
formed by linking said units. These polymers are useful in the
production of surgical products such as sutures, ligating clips,
and the like.
THE PRIOR ART
Kito et al., in Kogyo Kagaku Zasshi 1971, 74 (11), 2313-15 (CA 76,
45892c, 1972), report the preparation of
.omega.-(p-carboxyphenoxy)alkanoic acids and their dimethyl
esters.
U.S. Pat. No. 3,637,595 discloses liquid crystal copolyesters
prepared from terephthalic acid, hydroquinone, and p-hydroxybenzoic
acid. British Pat. Nos. 1,507,207 and 1,508,646 (equivalent to
German OS No. 2,520,820) disclose liquid crystal polyesters
prepared from a variety of dihydric phenols and aromatic
dicarboxylic acids.
In Shalaby et al., U.S. patent application Ser. No. 329,331, filed
June 29, 1982 and assigned to the same assignee as this
application, there is disclosed radiation sterilizable, absorbable
polymers derived from 1,4-phenylene-bis-oxyacetic acid, including
copolymers derived from poly(alkylene 1,4-phenylene-bis-oxyacetate)
and glycolide and/or lactide.
In Bezwada et al., U.S. patent application Ser. No. 459,428, filed
Jan. 20, 1983 now U.S. Pat. No. 4,510,295, and assigned to the same
assignee as this application, there is disclosed radiation
sterilizable, absorbable polymers derived from
4-(carboxymethoxy)benzoic acid and glycolide and/or lactide.
U.S. Pat. No. 2,516,955 (Butler et al.) discloses esters of
phenylene-bis-oxyacetic acid and monohydric alcohols.
Low molecular weight polyesters of phenylene-bis-oxyacetic acid are
claimed to have been produced by Spanagel and Carouthers, as
reported in JACS, 57, pages 935-936 (1935).
Doddi et al., in U.S. Pat. No. 4,052,988, discloses synthetic
absorbable sutures and other surgical devices produced from
polymers of p-dioxanone.
DETAILED DESCRIPTION OF THE INVENTION
The polymers of the invention are copolyesters that are preferably
produced by the reaction of (a) p-dioxanone monomer, and (b) a base
polyester of a dihydric alcohol and a phenylene-bis-oxyacetic acid
and/or a carboxymethoxybenzoic acid.
The preferred procedures for the preparation of the base polyesters
and the diacids or diesters used to make them are illustrated by
Examples 1-9:
EXAMPLE 1
Preparation of Dimethyl Ester of 4-(carboxymethoxy)benzoic Acid
##STR1##
152.2 Grams (1 mole) of methyl p-hydroxybenzoate, 130.2 grams (1.2
mole) of methyl chloroacetate, and 427 milliliters of anhydrous
methanol are charged into a 2-liter, 3-neck, round bottom flask
fitted with an addition funnel with a nitrogen inlet, a mechanical
stirrer, a reflux condenser with a drying tube, a thermometer, and
a heating mantle. The reaction mixture is refluxed for 30-60
minutes. A solution of sodium methoxide in methanol (216.1 grams,
25% by weight, or 1 mole of sodium methoxide) is added through the
addition funnel in 1-2 hours at reflux. After the addition is
completed, the stirred reaction mixture is refluxed for about 16
hours under nitrogen. One milliliter of glacial acetic acid is
added to make sure that the reaction mixture is not basic. The hot
solution is then filtered to remove the precipitated sodium
chloride. Upon cooling the mother liquor, white crystalline
material is precipitated. The crystals are filtered, dried, and are
then recrystallized twice from anhydrous methanol using 3.5
milliliters per gram of dried product. The product has a melting
point of 94.degree.-95.5.degree. C. with an overall yield of 163
grams of the dimethyl ester of 4-(carboxymethoxy)benzoic acid
(72.7%).
The corresponding 1,2- and 1,3-isomers are derived by analogous
procedures from methyl salicylate and methyl m-hydroxybenzoate,
respectively. In those aspects of the invention wherein R in the
divalent unit (C) is alkyl, a substituted alpha-chloroacetic ester
is used in place of methyl chloroacetate. Examples include methyl
alpha-chloropropionate, methyl alpha-chlorobutyrate, and methyl
alpha-chlorohexanoate.
The benzene ring in the hydroxybenzoic acid starting reactant can
contain substituent groups such as lower alkyl (e.g., methyl) or
lower alkoxy (e.g., methoxy) that do not interfere with the
esterification reactions to which the monomer will be subjected in
producing the copolyester of the invention.
EXAMPLE 2
Preparation of Dimethyl 1,4-Phenylene-bis-oxyacetate
A dry 5-liter, 3-neck round bottom flask equipped with an addition
funnel with a nitrogen inlet, a mechanical stirrer, and a reflux
condenser with drying tube, a thermometer and a heating mantle is
charged with 330.3 grams (3 moles) of hydroquinone, 651.2 grams (6
moles) of methyl chloroacetate, and 1722 ml. of methanol. The
contents of the flask are brought to reflux (approximately
68.degree. C.) after an initial purge with nitrogen. A solution of
sodium methoxide in methanol (1183 grams, 27.4 weight percent or 6
moles of sodium methoxide), is charged to the addition funnel and
allowed to slowly enter the refluxing reaction solution over the
course of approximately one hour.
After the addition is completed, the reaction mixture is allowed to
reflux an additional 17 hours during which time the reflux
temperature drops to 65.degree. C. Glacial acetic acid (about 2
milliliters) is added to make sure the solution is not basic. The
solution is filtered while hot (above 60.degree. C.) to remove the
precipitated sodium chloride. The filtrate is cooled and a white
crystalline material precipitates. The crystals are filtered and a
dry weight of 498.9 grams is obtained. The crystals are twice
recrystallized from methanol using 4 ml of methanol per gram of dry
weight of crystals to result in dimethyl
1,4-phenylene-bis-oxyacetate having a melting point of
97.degree.-98.degree. C., with an overall yield of at least
55.4%.
Just as was the case with the aspect of the invention illustrated
by Example 1, a substituted alpha-chloracetic acid ester can be
used to produce polymers wherein R in (C) is alkyl.
EXAMPLE 3
Preparation of the dimethyl ester of 1,3-phenylene-bis-oxyacetate
##STR2##
A dry 3-liter, 3-neck, round botton flask equipped with an addition
funnel, a nitrogen inlet, a reflux condenser with a drying tube,
and a mechanical stirrer, is charged with 220.2 grams (2 moles) of
resorcinol, 434.1 grams (4 moles) of methyl chloroacetate, and 798
milliliters of methanol. The contents of the flask are heated to
reflux for 30 minutes after an initial purge with nitrogen. A
solution of sodium methoxide in methanol (864.3 grams, 25.0 weight
percent or 4 moles of sodium methoxide) is charged to the addition
funnel, and added slowly to the refluxing reaction solution over
the course of approximately two hours.
After the addition is completed, the reaction mixture is allowed to
reflux an additional 17 hours. Two milliliters of glacial acetic
acid is added to render the reaction mixture mildly acidic. The
solution is hot filtered to remove the sodium chloride. Upon
cooling the filtrate, white crystalline material is precipitated.
The crystals are filtered and a dry weight of 296.0 grams is
obtained. The crystals are recrystallized using 3 milliliters of
methanol per gram of dry weight of crystals to result in 134 grams
of product. It was recrystallized again using 2 milliliters of
methanol per gram of dry crystals to result in dimethyl
1,3-phenylene-bis-oxyacetate having a melting point of
60.5.degree.-61.5.degree. C. and with an overall yield of 24.4
percent.
Preparation of Base Polyester
The base polyesters can be produced by a transesterification or an
esterification reaction between a dihydric alcohol of Formula
II:
and a compound of Formula III:
wherein G, Ph, and m have the meanings set forth above, and wherein
R is hydrogen or lower alkyl such as methyl, ethyl, or propyl, and
wherein R' is hydrogen, lower alkyl such as methyl, ethyl, or
isopropyl, or phenyl.
The dihydric alcohols that can be employed to produce the base
polyesters, which can be used singly or in mixtures, include
C.sub.2 to C.sub.8 alkylene glycols such as ethylene glycol, 1,2-
and 1,3-propylene glycol, 1,4-butylene glycol, 1,6-hexylene glycol,
and the like; polyalkylene glycols such as diethylene glycol,
triethylene glycol, poly(oxytetramethylene) glycol, and the like;
cycloaliphatic diols such as 1,4-cyclohexanedimethanol, and the
like; and aromatic dihydric alcohols such as
1,4-bis(2-hydroxyethoxy)benzene, and the like. The polymethylene
glycols having three to six carbon atoms are preferred.
1,3-Propylene glycol is most preferred.
The compounds of Formula III are preferably lower alkyl diesters
such as the dimethyl diesters, because they are the most convenient
to use in a transesterification reaction. The corresponding half
esters or diacids can also be used, if desired, but are usually not
preferred.
The dihydric alcohol and the diester (or half ester or diacid) are
usually reacted in proportions of from about 1.1 to about 4 moles
of dihydric alcohol per mole of diester (or half ester or
diacid).
A catalytically effective amount of a transesterification catalyst,
with or without an esterification catalyst, is used in the
reaction. While the reaction would proceed with a wide variety of
such catalysts, as a practical matter because the polymers of the
invention are intended for use in absorbable products, biologically
acceptable catalysts used in very small amounts are preferred.
Specific examples of such catalysts are stannous octoate and
dibutyltin oxide. Illustrative proportions are from about 750 to
about 30,000, and preferably about 1500 to about 15,000 moles of
monomer (i.e., moles of the compound of Formula III) per mole of
catalyst.
EXAMPLE 4
Preparation of polyester of 1,3-propylene glycol and
1,4-phenylene-bis-oxyacetic acid ##STR3##
Under a dry nitrogen atmosphere, the following materials were
charged into a flame and vacuum dried, two-liter, three-neck, round
bottom flask, equipped with a vacuum tight stainless steel paddle
stirrer, a short distillation head fitted with a receiver, and an
adapter with a hose connection:
444.5 grams Dimethyl 1,4-Phenylene-bis-oxyacetate (1.75 moles)
336.8 grams 1,3-Propanediol (4.42 moles)
0.0253 gram Stannous Octoate (6.25.times.10.sup.-5 mole)
(In this Example and in other Examples where it is used, the
stannous octoate is added as a solution in toluene.)
After stoppering the flask, the contents of the flask were purged
with nitrogen and then subjected to reduced pressure for several
hours. The charged reaction vessel was then vented with nitrogen,
closed off, and placed in an oil bath. Under nitrogen at one
atmosphere pressure, the reaction mixture was melted using a bath
temperature of 120.degree. C.
Once the charge was liquified, the reaction flask was connected to
an efficient mechanical stirrer and thorough mixing at 120.degree.
C. was performed for one-half hour. While still under an atmosphere
of nitrogen, the molten PG,11 reactants were subjected to the
following heating sequence: 160.degree. C. for 1.25 hours;
175.degree. C. for 1.5 hours; 190.degree. C. for 2.5 hours;
205.degree. C. for 2 hours; and 220.degree. C. for 2.25 hours.
After the 2.25 hours at 220.degree. C., the receiver containing the
distillate was replaced with an empty receiver. Gradually over the
course of 0.75 hour, the pressure in the reaction vessel was
reduced to 0.05 millimeter of mercury. Under reduced pressure, the
reaction mixture was heated at 220.degree. C. for a total of 22.5
hours. The reaction flask was removed from the oil bath,
equilibrated with nitrogen, and then allowed to cool to room
temperature. The soft polymer was isolated by first chilling the
flask in liquid nitrogen to freeze the polymer, breaking the flask,
and collecting the frozen polymer.
The polyester was amorphous and had an inherent viscosity of 0.84
dl/gm, measured at 25.degree. C. at a concentration of 0.1 gm/dl in
hexafluoroisopropyl alcohol ("HFIP").
EXAMPLE 5
Preparation of polyester of 1,3-propylene glycol and
1,4-phenylene-bis-oxyacetic acid Under a dry nitrogen atmosphere,
the following materials were charged to a flame and vacuum dried,
one-liter, three-neck, round bottom flask, equipped with a vacuum
tight stainless steel paddle stirrer, a short distillation head
fitted with a receiver, and an adapter with a hose connection:
254 grams Dimethyl 1,4-phenylene-bis-oxyacetate (1.0 mole)
190.2 grams 1,3-Propanediol (2.5 moles)
0.0144 gram Stannous Octoate (3.56.times.10.sup.-5 mole)
After stoppering the flask, the contents of the flask were purged
with nitrogen and then subjected to reduced pressure for several
hours. The charged reaction vessel was then vented with nitrogen,
closed off, and then placed in an oil bath. Under nitrogen at one
atmosphere pressure, the reaction mixture was melted using a bath
temperature of 120.degree. C. Once the charge was liquified, the
reaction flask was connected to an efficient mechanical stirrer and
thorough mixing at 120.degree. C. was performed for one-half hour.
While still under an atmosphere of nitrogen, the molten reaction
mixture was subjected to the following heating sequence:
160.degree. C. for 1.0 hour; 175.degree. C. for 1.0 hour;
190.degree. C. for 2.0 hours; 205.degree. C. for 2.5 hours; and
220.degree. C. for 2.0 hours.
After the 2.0 hours at 220.degree. C., the receiver containing the
distillate was replaced with an empty receiver. Gradually over the
course of 0.75 hour, the pressure in the reaction vessel was
reduced to 0.05 millimeter of mercury. Under reduced pressure, the
reaction mixture was heated at 220.degree. C. for a total of 11.25
hours. After this step, the reaction flask was removed from the oil
bath, equilibrated with nitrogen, and then allowed to cool to room
temperature. The soft polymer was isolated after chilling in liquid
nitrogen as described above.
The polyester was amorphous and had an inherent viscosity of 0.81
dl/gm in HFIP.
EXAMPLE 6
Preparation of Polyester of 1,6-hexanediol and
1,4-phenylene-bis-oxyacetic acid ##STR4##
Under a dry nitrogen atmosphere, the following materials were
charged to a flame and vacuum dried, 250-ml, round bottom flask,
equipped with a vacuum tight stainless steel paddle stirrer, a
short distillation head fitted with a receiver, and an adapter
fitted with a hose connection:
50.8 grams Dimethyl 1,4-phenylene-bis-oxyacetate (0.20 mole)
24.8 grams 1,6-Hexanediol (0.21 mole)
0.0036 gram Dibutyltin Oxide (1.45.times.10.sup.-5 mole).
After stoppering the flask, the contents of the flask were purged
with nitrogen and then subjected to reduced pressure for several
hours. The charged reaction vessel was then vented with nitrogen,
closed off, and placed in an oil bath. While under nitrogen at one
atmosphere, the stirred molten reactants were subjected to the
following heating sequence: 160.degree. C. for 1.5 hours;
190.degree. C. for 0.5 hour; and 220.degree. C. for 1.0 hour.
After the 1.0 hour at 220.degree. C., the receiver containing the
distillate was replaced with an empty receiver. Gradually over the
course of 0.75 hour, the pressure in the reaction vessel was
reduced to 0.05 millimeter of mercury. Under reduced pressure, the
reaction mixture was heated at 220.degree. C. for 1.5 hours and at
230.degree. C. for 3.5 hours. After this step, the reaction flask
was removed from the oil bath, equilibrated with nitrogen, and then
allowed to cool to room temperature. The soft polymer was isolated
after chilling in liquid nitrogen, as described above. The
polyester had a melting point of 65.degree.-70.degree. C. and an
inherent viscosity of 0.36 dl/gm in HFIP.
EXAMPLE 7
Preparation of Polyester of 1,6-hexanediol and
1,4-phenylene-bis-oxyacetic acid ##STR5##
Under a dry nitrogen atmosphere, the following materials were
charged to a flame and vacuum dried, 250-ml, two-neck, round bottom
flask, equipped with a vacuum tight stainless steel paddle stirrer,
a short distillation head fitted with a receiver, and an adapter
fitted with a hose connection:
50.8 grams Dimethyl 1,4-Phenylene-bis-oxyacetate (0.20 mole)
24.8 grams 1,6-hexanediol (0.21 mole)
0.0036 gram Dibutyltin Oxide (1.45.times.10.sup.-5 mole).
After stoppering the flask, the contents were purged with nitrogen
and then exposed to reduced pressure for several hours. The charged
reaction vessel was vented with nitrogen, closed off, and placed in
an oil bath. Under an atmosphere of nitrogen, the reaction mixture
was melted using a bath temperature of 120.degree. C. Once the
charge was liquified, the reaction flask was connected to an
efficient mechanical stirrer and thorough mixing at 120.degree. C.
was performed for one-half hour. While still under nitrogen, the
molten reactants were subjected to the following heating sequence:
160.degree. C. for 1.5 hours; 190.degree. C. for 0.5 hours; and
220.degree. C. for 1.0 hour.
After the 1.0 hour at 220.degree. C., the receiver containing the
distillate was replaced with an empty receiver. Then gradually over
the course of 0.75 hour, the pressure in the reaction vessel was
reduced to 0.05 millimeter of mercury. Under reduced pressure, the
reaction mixture was heated at 220.degree. C. for 1.0 hour. After
this step, the reaction flask was removed from the oil bath,
equilibrated with nitrogen, and then allowed to cool to room
temperature. The soft polymer was isolated after chilling in liquid
nitrogen as described above. The polyester had a melting point of
70.degree.-75.degree. C. and an inherent viscosity in HFIP of 0.63
dl/gm.
EXAMPLE 8
Preparation of Polyester From 1,3-Propanediol and dimethyl
1,3-phenylene-bis-oxyacetate ##STR6##
A flame dried, mechanically stirred, 250-milliliter glass reactor
(suitable for polycondensation reaction) is charged with 63.6 grams
(0.25 mole) of dimethyl 1,3-phenylene-bis-oxyacetate, 57.1 grams
(0.75 mole) of 1,3-propanediol, and 0.114 ml. of 0.33M stannous
octoate in toluene (0.015 mole percent based on the diester
monomer). After purging the reactor and venting with nitrogen, the
contents of the reaction flask are melted using an oil bath
temperature of 165.degree. C. The temperature of the oil bath is
raised to 210.degree. C. in 30 minutes and is maintained at
210.degree. C. for 2 hours, and at 220.degree. C. for 3 hours while
still under a nitrogen atmosphere, during which time the methanol
formed is collected. The reactor is allowed to cool to room
temperature overnight. The next day, the reaction flask is heated
slowly under reduced pressure (0.015-1.0 mm) to 210.degree. C.
within 6 to 8 hours, and is maintained for 4 hours at 210.degree.
C., during which time the distillates are collected. The polymer is
isolated, ground, and dried in a vacuum oven at room temperature.
The resulting polymer has an inherent viscosity of 0.60 dl/g in
hexafluoroisopropyl alcohol at 25.degree. C. and 0.1 g/dl
concentration.
EXAMPLE 9
Preparation of polyester of 1,3-propanediol and
4-(carboxymethoxy)benzoic acid ##STR7##
A flame dried, mechanically stirred, 100-milliliter glass reactor
(suitable for polycondensation reactions) is charged with 89.7
grams (0.4 mole) of the dimethyl ester of 4-(carboxymethoxy)benzoic
acid, 76.10 grams (1.0 mole) of 1,3-propanediol, and 7.16
milligrams of dibutyltin oxide. After purging the reactor and
venting with nitrogen, the contents of the reaction flask are
melted in an oil bath at 160.degree. C. The temperature of the oil
bath is raised to 190.degree. C. in 2 hours and is maintained at
190.degree. C. for 2 hours and then at 210.degree. C. for 2 hours,
during which time the methanol formed is collected. The reactor is
allowed to cool to room temperature overnight. The next day, the
reaction flask is heated slowly under reduced pressure (0.05-1.0
mm) to 210.degree. C. within 3 hours and 30 minutes, and is
maintained for 4 hours and 15 minutes at 210.degree. C., during
which time the distillates are collected. The polymer is isolated,
ground, and dried in a vacuum oven at room temperature. The
resulting polymer has an inherent viscosity of 0.58 dl/g in
hexafluoroisopropyl alcohol at 25.degree. C. and 0.1 g/dl
concentration.
The base polyesters are usually essentially noncrystalline
materials, or display low levels of crystallinity, having molecular
weights in excess of about 2000, and having inherent viscosities of
at least about 0.2 dl/gm, tested at a concentration of 0.1 gm/dl in
hexafluoroisopropyl alcohol at 25.degree. C.
Preparation of Copolyester
The copolyesters of the invention are produced by reacting the base
polyester with p-dioxanone. The co-esterification reaction is
preferably carried out by dissolving the polyester in p-dioxanone,
and then subjecting the reaction mixture to elevated temperature
for a period of time sufficient to produce the copolyester of the
invention. An additional esterification catalyst system may be
added for this second polymerization, or the initial catalyst that
remains in the reaction mixture from the preparation of the base
polyester may be sufficient to catalyze the reaction.
The proportion of polyester to p-dioxanone is selected so that the
resulting copolyester will be absorbable and will be able to
withstand radiation sterilization while still maintaining a useful
level of physical and biological properties. Typically, the
copolyester will contain from about 59 to 99 weight percent, and
preferably (for suture applications) from 75 to 90 weight percent,
of polymerized p-dioxanone. Routine experimentation will suffice to
determine the proportions of base polyester and p-dioxanone monomer
that should be used in particular cases to achieve the desired
proportion in the copolyester product. The Examples herein
illustrate typical percent conversions of monomer. It is noted that
solid state polymerization (e.g., Example 11) usually yields a
higher percent converstion than melt polymerization (e.g., Example
10).
The following Examples 10-19 illustrate the preparation of the
copolyesters:
EXAMPLE 10
Preparation of copolyester of p-dioxanone and polyester of
1,3-propanediol and 1,4-phenylene-bis-oxyacetic acid
To a dry, 250-milliliter, single-neck, round bottom flask was added
9.0 grams of poly(trimethylene 1,4-phenylene-bis-oxyacetate) having
an inherent viscosity in hexafluoroisopropyl alcohol of 0.81
dl/gram (Example 5). The contents of the flask were dried by
exposure to high vacuum (less than 0.05 millimeter of mercury) for
several hours at room temperature, followed by heating at
110.degree. C. for 16 hours under high vacuum. The following
materials were then added to the dried contents of the flask, under
a dry nitrogen atmosphere:
57.6 grams p-dioxanone (0.565 mole)
0.0076 gram Stannous Octoate (1.88.times.10.sup.-5 mole).
A flame dried vacuum tight stainless steel paddle stirrer and an
adapter with a hose connection were attached to the charged
reaction flask, and the pressure in the reaction assembly was
reduced to a low level for several hours. The reaction flask was
then vented with nitrogen, closed off, and placed in an oil bath.
Under an atmosphere of dry nitrogen, the reaction mixture was
heated, with initially rapid mechanical stirring to facilitate
dissolution of the polyester in the monomer, according to the
following temperature/time sequence:
80.degree. C./1.75 hrs.
100.degree. C./7.25 hrs.
(The stirring rate was slowed as the viscosity of the polymerizing
mass increased.)
The resulting copolyester was isolated after chilling in liquid
nitrogen as described above, and then ground. After exposure to
vacuum at room temperature for 16 hours, the ground copolyester was
heated at 80.degree. C. and a pressure of 0.05 millimeter of
mercury for 26 hours to remove unreacted p-dioxanone from the
desired copolyester product; a 35.9% weight loss was observed.
(Removal of unreacted monomer can also be effected by vented screw
extrusion. This latter procedure is preferred when the content of
unreacted monomer is relatively high, e.g., over 15 weight
percent.) The resulting copolyester product had an inherent
viscosity of 1.87 dl/gm measured at 25.degree. C. and a
concentration of 0.1 gram/dl in hexafluoroisopropyl alcohol.
EXAMPLE 11
Preparation of copolyester of p-dioxanone and polyester of
1,3-propanediol and 1,4-phenylene-bis-oxyacetic acid To a dry,
100-milliliter, single-neck, round bottom flask was added 4.14
grams of poly(trimethylene 1,4-phenylene-bis-oxyacetate) having an
inherent viscosity in hexafluoroisopropyl alcohol of 0.87 dl/gram.
The contents of the flask were dried by exposure to high vacuum
(less than 0.05 millimeter of mercury) for several hours at room
temperature, followed by heating at 90.degree. C. for 15 hours
under high vacuum. The following materials were next added to the
dried contents of the flask, under a dry nitrogen atmosphere:
23.5 grams p-Dioxanone (0.23 mole)
0.00468 gram Stannous Octoate (1.16.times.10.sup.-5 mole).
A flame dried vacuum tight stainless steel paddle stirrer and an
adapter with a hose connection were attached to the charged
reaction flask, and the pressure in the reaction assembly was
reduced to a low level for several hours. The reaction flask was
vented with nitrogen, closed off, and placed in an oil bath. Under
dry nitrogen at one atmosphere, the reaction mixture was heated,
with initially rapid mechanical stirring, according to the
following temperature/time sequence:
80.degree. C./1.0 hr.
90.degree. C/27.0 hrs.
80.degree. C./88.0 hrs.
(Stirring was slowed and eventually stopped when the viscosity of
the polymerizing mass became so great as to virtually prevent
further stirring.)
The resulting copolyester was isolated after chilling in liquid
nitrogen as described above, and then ground. After exposure to
vacuum at room temperature for 16 hours, the ground copolyester was
heated at 80.degree. C. and a pressure of 0.05 millimeter of
mercury for 16 hours to remove unreacted p-dioxanone from the
desired copolyester product; an 8.6% weight loss was observed. The
resulting copolyester product had an inherent viscosity of 1.84
dl/gm measured at 25.degree. C. at a concentration of 0.1 gram/dl
in hexafluoroisopropyl alcohol, and a melting point of
105.degree.-111.degree. C. (by thermal microscopy).
EXAMPLE 12
Preparation of copolyester of p-dioxanone and polyester of
1,3-propanediol and 1,4-phenylene-bis-oxyacetic acid
To a dry, 250-milliliter, single-neck, round bottom flask was added
9.0 grams of poly(trimethylene 1,4-phenylene-bis-oxyacetate) having
an inherent viscosity in hexafluorisopropyl alcohol of 0.63
dl/gram. The contents of the flask were dried by exposure to a high
vacuum (less than 0.05 millimeter of mercury) for several hours at
room temperature, followed by heating at 90.degree. C. for 12 hours
under high vacuum. The following materials were then added to the
dried contents of the flask, under a dry nitrogen atmosphere:
81.0 grams p-Dioxanone (0.794 mole)
0.0160 gram Stannous Octoate (3.96.times.10.sup.-5 mole).
A flame dried vacuum tight stainless steel paddle stirrer and an
adapter with a hose connection were attached to the charged
reaction flask, and the pressure in the reaction assembly was
reduced to a low level for several hours. The reaction flask was
then vented with nitrogen and placed in an oil bath. Under a dry
nitrogen atmosphere, the reaction mixture was heated, with
initially rapid mechanical stirring, according to the following
temperature/time sequence:
80.degree. C./1.0 hr.
90.degree. C./27.0 hrs.
80.degree. C./88.0 hrs.
(Stirring was slowed and eventually stopped when the viscosity of
the polymerizing mass became so great as to virtually prevent
further stirring.)
The resulting copolyester was isolated after chilling in liquid
nitrogen, and was then ground. After exposure to vacuum at room
temperature for 16 hours, the ground copolyester was heated at
80.degree. C. and a pressure of 0.05 millimeter of mercury for 16
hours to remove unreacted p-dioxanone from the desired copolyester
product; an 11.2% weight loss was observed. The resulting
copolyester product had an inherent viscosity of 1.74 dl/gm
measured at 25.degree. C. at a concentration of 0.1 gram/dl in
hexafluoroisopropyl alcohol, and a melting point (by thermal
microscopy) of 107.degree.-111.degree. C.
EXAMPLE 13
Preparation of copolyester of p-dioxanone and polyester of
1,3-propanediol and 1,4-phenylene-bis-oxyacetic acid
To a dry, 2-liter, three-neck, round bottom flask was added 75.0
grams of poly(trimethylene 1,4-phenylene-bis-oxyacetate) having an
inherent viscosity in hexafluoroisopropyl alcohol of 0.81 dl/gram
(Example 5). The contents of the flask were dried by exposure to
high vacuum (less than 0.05 millimeter of mercury) for several
hours at room temperature, followed by heating at 110.degree. C.
for 16 hours under high vacuum. The following materials were added
to the dried contents of the flask, under a dry nitrogen
atmosphere:
425.0 grams p-Dioxanone (4.17 moles)
0.0842 gram Stannous Octoate (2.08.times.10.sup.-4 mole).
A flame dried vacuum tight stainess steel paddle stirrer and an
adapter with a hose connection were attached to the charged
reaction flask, and the pressure in the reactor was reduced to a
low level for several hours. The reaction flask was vented with
nitrogen, closed off, and placed in an oil bath. Under a dry
nitrogen atmosphere, the reaction mixture was heated, with
initially rapid mechanical stirring, according to the following
temperature/time sequence:
75.degree. C./2.25 hrs.
90.degree. C./3.0 hrs.
80.degree. C./135 hrs.
(Stirring was slowed and eventually stopped when the viscosity of
the polymerizing mass became so great as to virtually prevent
further stirring.) The resulting copolyester was isolated after
chilling in liquid nitrogen, and then ground. After exposure to
vacuum at room temperature for 16 hours, the ground copolyester was
heated at 80.degree. C. and a pressure of 0.05 millimeter of
mercury for 62 hours to remove unreacted p-dioxanone from the
desired copolyester product; an 11.8% weight loss was observed. The
resulting copolyester product had an inherent viscosity of 2.18
dl/gm measured at 25.degree. C. and a concentration of 0.1 gram/dl
and 25.degree. C. in hexafluoroisopropyl alcohol, and a melting
point (by thermal microscopy) of 109.degree.-111.degree. C.
EXAMPLE 14
Preparation of copolyester of p-dioxanone and polyester of
1,6-hexanediol and 1,4-phenylene-bis-oxyacetic acid
To a dry, 500-milliliter, single-neck, round bottom flask was added
4.5 grams of poly(hexamethylene 1,4-phenylene-bis-oxyacetate)
having an inherent viscosity in hexafluoroisopropyl alcohol of 0.63
dl/gram (Example 7). The contents of the flask were dried by
exposure to high vacuum (less than 0.05 millimeter of mercury) for
several hours at room temperature, followed by heating at
90.degree. C. for 15 hours under high vacuum. The following
materials were added to the dried contents of the flask, under a
dry nitrogen atmosphere:
85.5 grams p-Dioxanone (0.838 mole)
0.0170 gram Stannous Octoate (4.19.times.10.sup.-5 mole).
A flame dried vacuum tight stainless steel paddle stirrer and an
adapter with a hose connection were attached to the charged
reaction flask, and the pressure in the reactor was reduced to a
low level for several hours. The reaction flask was vented with
nitrogen, closed off, and placed in an oil bath. Under a dry
nitrogen atmosphere, the reaction mixture was heated, with
initially rapid mechanical stirring, according to the following
temperature/time sequence:
80.degree. C./1.0 hr.
90.degree. C./27.0 hrs.
80.degree. C./88.0 hrs.
(Stirring was slowed and eventually stopped when the viscosity of
the polymerizing mass became so great as to virtually prevent
further stirring.)
The resulting copolyester was isolated after chilling in liquid
nitrogen, and then ground. After exposure to vacuum at room
temperature for 16 hours, the ground copolyester product was heated
at 80.degree. C. and a pressure of 0.05 millimeter of mercury for
16 hours to remove unreacted p-dioxanone from the desired
copolyester product; a 3.9% weight loss was observed. The resulting
copolyester product had an inherent viscosity of 2.29 dl/gm
measured at 25.degree. C. at a concentration of 0.1 gram/dl in
hexafluoroisopropyl alcohol, and a melting point of
104.degree.-114.degree. C. (by thermal microscopy).
EXAMPLE 15
Preparation of copolyester of p-dioxanone and polyester of
1,6-hexanediol and 1,4-phenylene-bis-oxyacetic acid
To a dry, 100-milliliter, single-neck, round bottom flask was added
3.0 grams of poly(hexamethylene 1,4-phenylene-bis-oxyacetate)
having an inherent viscosity in hexafluoroisopropyl alcohol of 0.36
dl/gram (Example 6). The contents of the flask were dried by
exposure to high vacuum (less than 0.05 millimeter of mercury) for
several hours at room temperature, followed by heating at
90.degree. C. for 15 hours under high vacuum. The following
materials were added to the dried contents of the flask, under a
dry nitrogen atmosphere:
27.0 grams p-Dioxanone (0.265 mole)
0.00534 gram Stannous Octoate 1.32.times.10.sup.-5 mole).
A flame dried vacuum tight stainless steel paddle stirrer and an
adapter with a hose connection were attached to the charged
reaction flask, and the pressure in the reactor was reduced to a
low level for several hours. The reaction flask was vented with
nitrogen, closed off, and placed in an oil bath. Under a dry
nitrogen atmosphere, the reaction mixture was heated, with
initially rapid mechanical stirring, according to the following
temperature/time sequence:
80.degree. C./0.75 hr.
90.degree. C./3.3 hrs.
80.degree. C./112 hrs.
(Stirring was slowed and eventually stopped when the viscosity of
the polymerizing mass became so great as to virtually prevent
further stirring.)
The resulting copolyester was isolated after chilling in liquid
nitrogen, and then ground. After exposure to vacuum at room
temperature for 16 hours, the ground copolyester product was heated
at 80.degree. C. and a pressure of 0.05 millimeter of mercury for
16 hours to remove unreacted p-dioxanone from the desired
copolyester product; a 11.2% weight loss was observed. The
copolyester product had an inherent viscosity of 1.82 dl/gm
measured at 25.degree. C. at a concentration of 0.1 gram/dl in
hexafluoroisopropyl alchol, and a melting point (by thermal
microscopy) of 109.degree.-112.degree. C.
EXAMPLE 16
Preparation of coplyester of p-dioxanone and polyester of
1,3-propanediol and 1,3-phenylene-bis-oxyacetic acid
A flame dried, 100-milliliter, round bottom, one-neck flask is
charged under nitrogen with 5 grams of the polyester of Example 8
and the contents of the flask are held for about 16 hours at
115.degree. C./0.1 mm. To the same flask, after drying, 45 grams of
p-dioxanone and 0.58 ml of 0.033M stannous octoate in toluene
(0.00434 mole percent, based on p-dioxanone monomer) are charged
and then the flask is fitted with a vacuum tight mechanical
stirrer. The flask is dried under vacuum and purged with nitrogen
three times before being vented with nitrogen and immersed in a
silicone oil bath. The mixture is heated to and maintained at about
85.degree. C. with rapid stirring for one hour to melt the
p-dioxanone and to dissolve the polyester. The temperature of the
oil bath is raised to 90.degree. C. and maintained for 24 hours at
90.degree. C. The mechanical stirring is discontinued after 3 to 4
hours at 90.degree. C. because of the viscous nature of the
reaction mass. The temperature of the oil bath is lowered to
80.degree. C. and is maintained there for 72 hours. The polyner is
isolated, ground, and dried 18 hours/80.degree. C./0.1 mm to remove
any unreacted monomer. A weight loss of 10.1% is observed. The
resulting polymer has a melting range of about
104.degree.-107.degree. C. and an inherent viscosity of about 2.2
dl/g at 25.degree. C. and a concentration of 0.1 g/dl in
hexafluoroisopropyl alcohol.
EXAMPLE 17
Preparation of copolyester of p-dioxanone and polyester of
1,3-propanediol and 4-(carboxymethoxy)benzoic acid
A flame dried, 250 milliliter, round bottom, one-neck flask is
charged under nitrogen with 10 grams of the polyester of Example 9
and the flask is held for about 16 hours at 50.degree. C./0.1 mm.
To the same flask, after drying, 90 grams of p-dioxanone and 0.133
ml of 0.33M stannous octoate in toluene (0.005 mole percent, based
on p-dioxanone monomer) are charged and then the flask is fitted
with a mechanical stirrer. The flask is dried under vacuum and
purged with nitrogen three times before being vented with nitrogen
and immersed in a silicone oil bath. The mixture is heated to and
maintained at about 85.degree. C. with rapid stirring for one hour
to melt the p-dioxanone and to dissolve the polyester. The
temperature of the oil bath is raised to 90.degree. C. and
maintained for 24 hours at 90.degree. C. The mechanical stirring is
discontinued after 3 to 4 hours at 90.degree. C. because of the
viscous nature of the reaction mass. The temperature of the oil
bath is lowered to 80.degree. C. and is maintained there for 72
hours. The polymer is isolated, ground, and dried for 36
hours/80.degree. C./0.1 mm to remove any unreacted monomer. A total
of 12.72% monomer is removed due to drying. The resulting polymer
has a melting range of about 106.degree.-110.degree. C. and an
inherent viscosity of about 1.88 dl/g at 25.degree. C. and a
concentration of 0.1 g/dl in hexafluoroisopropyl alcohol.
EXAMPLE 18
Preparation of copolyester of p-dioxanone and polyester of
1,3-propanediol and 1,3-phenylene-bis-oxyacetic acid
A flame dried, 250-milliliter, round bottom, one-neck flask is
charged under nitrogen with 15 grams of the polyester of Example 8
and the contents of the flask are held for about 16 hours at
115.degree. C./0.1 mm. To the same flask, after drying, 85 grams of
p-dioxanone and 0.10 milliliter of 0.33M stannous octoate in
toluene (0.00396 mole percent based on p-dioxanone monomer) are
charged and the flask is fitted with a flame dried mechanical
stirrer and an adapter with a hose connection. The reactor is
purged with nitrogen three times before being vented with nitrogen.
The reactor is connected to a gas supply to maintain nitrogen at a
pressure of one atmosphere for the remainder of the run and then is
immersed in a silicone oil bath. The mixture is heated to and
maintained at about 80.degree. C. for one hour to melt the
p-dioxanone and to dissolve the polyester. The temperature of the
oil bath is raised to 90.degree. C. and is maintained there for 24
hours. The mechanical stirring is discontinued after 3 to 4 hours
at 90.degree. C. because of the viscous nature of the reaction
mass. The temperature of the oil bath is lowered to 80.degree. C.
and maintained there for 72 hours. The polymer is isolated, ground,
and dried 18 hours/80.degree. C./0.1 mm to remove any unreacted
monomer. A weight loss of 12.8% is observed. The resulting polymer
has a melting range of about 105.degree.-108.degree. C. and an
inherent viscosity of about 1.82 dl/g at 25.degree. C. and a
concentration of 0.1 g/dl in hexafluoroisopropyl alcohol.
EXAMPLE 19
Preparation of copolyester of p-dioxanone and polyester of
1,3-propanediol and 4-(carboxymethoxy)benzoic acid
A flame dried, 250-milliliter, round bottom, one-neck flask is
charged under nitrogen with 15 grams of the polyester of Example 9
and the flask is held for about 16 hours at 50.degree. C./0.1 mm.
To the same flask, after drying, 85 grams of p-dioxanone and 0.126
milliliter of 0.33M stannous octoate in toluene (0.005 mole
percent, based on p-dioxanone monomer) are charged and the flask is
fitted with a mechanical stirrer and an adapter with a hose
connection. The reactor is purged with nitrogen three times before
being vented with nitrogen. The reactor is connected to a gas
supply to maintain nitrogen at a pressure of one atmosphere for the
remainder of the run and then is immersed in a silicone oil bath.
The mixture is heated to and maintained at about 75.degree. C. for
one hour to melt the p-dioxanone and to dissolve the polyester. The
temperature of the oil bath is raised to 90.degree. C. and is
maintained there for 24 hours. The mechanical stirring is
discontinued after 3 to 4 hours at 90.degree. C. because of the
viscous nature of the reaction mass. The temperature of the oil
bath is lowered to 80.degree. C. and is maintained there for 72
hours. The polymer is isolated, ground, and dried for 18
hours/80.degree. C./0.1 mm to remove any unreacted monomer. A total
of 5.79% monomer is removed. The resulting polymer has a melting
range of about 107.degree.-109.degree. C. and an inherent viscosity
of about 1.56 dl/g at 25.degree. C. and a concentration of 0.1 g/dl
in hexafluoroisopropyl alchol.
Control 1
Under a dry nitrogen atmosphere, p-dioxanone (155.2 grams, 1.52
moles), 1-dodecanol (0.473 gram, 2.54 millimoles, 4.73 milliters of
a 0.537 M toluene solution), and a catalytic amount of stannous
octoate (0.115 milliliter of a 0.33 M toluene solution, 0.038
millimoles) were added to a flame and vacuum dried 500 milliliter
glass ampoule, equipped with a magnetic stirring bar. The contents
of the ampoule were exposed to vacuum at room temperature for
several hours with intermittant dry nitrogen purges. The glass
ampoule was sealed under partial vacuum, placed in a silicone oil
bath, and its contents heated (with rapid magnetic mixing as
melting viscosity allowed) according to the following
temperature/time scheme:
120.degree. C./1 Minute
90.degree. C./3 Hours
80.degree. C./96 Hours.
The resulting polyester was isolated by immersing the glass ampoule
in liquid nitrogen and shattering the surrounding glass with a
heavy object. The glass-free polymer was ground in a Wiley mill and
stored under vacuum for 16 hours at room temperature. The ground
polymer was heated at 80.degree. C. under a pressure of 0.05
millimeters of mercury for 16 hours to remove any unreacted
p-dioxanone. The polyester possessed an inherent viscosity of 1.79
dl/gm measured at 25.degree. C. and a concentration of 0.1 gram/dl
in hexafluoroisopropyl alcohol.
The control polyester was spun at 155.degree. C. at a shear rate of
213 sec.sup.-1 using an INSTRON Capillary Rheometer with a 40 mil
die (L/D=24.1) and a ram speed of 2 cm/min. An apparent melt
viscosity of 6715 poise was observed. The fiber was taken up at 24
feet/minute after an ice water quench; the wound fiber was dried
and subsequently drawn one week later.
The control extrudate (diameter range: 17.0 to 18.5 mils) was drawn
in two stages employing a glycerine draw bath under the conditions
of 4.times. at 55.degree. C. followed by 1.5.times. at 75.degree.
C. and subsequently water-washed and dried in vacuo at room
temperature.
The control drawn monofilaments were annealed at 77.degree. C. for
6 hours with 5% relaxation.
The control annealed monofilaments were cut to appropriate lengths,
placed in individual paper folders and heat-sealable vented foil
envelopes. The packages were subjected to 50.degree. C. and 0.1 mm
Hg pressure for 72 hours to dry and subsequently sealed under
nitrogen. Portions of the control packaged fibers were sterilized
by exposure to 2.5Mrads of gamma radiation from a Co.sup.60
source.
EXTRUSION
The copolyesters are melt extruded through a spinnerette in a
conventional manner to form one or more filaments.
Extrusion of the copolyesters described herein was accomplished
using an INSTRON Capillary Rheometer. The copolymers were packed in
the preheated (80.degree. to 90.degree. C.) extrusion chamber and
extruded through a 40 mil die (L/D=24.1) after a dwell time of 11
to 13 minutes at the extrusion temperature and a ram speed of 2
cm/min. While extrusion temperatures depend both on the polymer Tm
and on the melt viscosity of the material at a given temperature,
extrusion of the subject copolyesters at temperatures of about
10.degree. to 75.degree. C. above the Tm is usually satisfactory.
The extrusion temperatures of the example copolyesters described
herein ranged from 155.degree. to 185.degree. C. The extrudate was
taken up through an ice water quench bath at either 24, 28 or 38.5
feet/minute. A screw-type extruder or similar device can be
substituted for the INSTRON Capillary Rheometer.
The extrudate filaments are subsequently drawn about 4.times. to
7.times. in a one or multistage drawing process in order to achieve
molecular orientation and improve tensile properties. The
extrudates described herein were drawn 2 hours to about 1 week
after extrusion. (The length of time elapsed between extrusion and
drawing may effect the drawing process; the optimum time elapsed is
easily determined by simple experimentation for each fiber
composition.) The manner of drawing is as follows:
The extrudate (diameter range, 13-20 mils) passed through rollers
at an input speed of four feet per minute and into a heated draw
bath of glycerine. The temperatures of the draw bath can vary from
about 25.degree. to 90.degree. C.; the examples described herein
employ temperatures between 52.degree. and 61.degree. C. The draw
ratio in this first stage of drawing can vary from 3.times. to
about 7.times.; the examples described herein employ draw ratios
from 4.times. to 5.times.. The partially drawn fibers are then
placed over a second set of rollers into a glycerine bath (second
stage) kept at temperatures ranging from 50.degree. to 95.degree.
C.; the examples described herein employ second stage draw
temperatures of 69.degree. to 84.degree. C. Draw ratios of up to
2.times. are applied in this second stage, but a ratio range of
from 1.2.times. to 1.5.times. has been employed in the examples.
The fiber is passed through a water-wash, taken up on a spool, and
dried. A set of hot rollers can be substituted for a portion or all
of the glycerine draw bath. The resulting oriented filaments have
good straight and dry tensile strengths.
Dimensional stability and tensile strength retention of the
oriented filaments may be enhanced by subjecting the filaments to
an annealing treatment. This optional treatment consists of heating
the drawn filaments to a temperature of from about 40.degree. to
90.degree. C., most preferably from about 60.degree. to 80.degree.
C. while restraining the filaments to prevent any substantial
shrinkage. This process may begin with the filaments initially
under tension or with up to 20% shrinkage allowed prior to
restraint. The filaments are held at the annealing temperature for
a few seconds to several days or longer depending on the
temperature and processing conditions. In general, annealing at
60.degree. to 80.degree. C. for up to about 24 hours is
satisfactory for the copolyesters of the invention. Optimum
annealing time and temperature for maximum fiber in vivo strength
retention and dimensional stability is readily determined by simple
experimentation for each fiber composition.
The characteristic properties of the filaments of the invention are
readily determined by conventional test procedures. The tensile
properties (i.e., straight and knot tensile strengths, Young's
Modulus, and elongation) displayed herein were determined with an
INSTRON tensile tester. The settings used to determine the straight
tensile, knot tensile, break elongation, and Young's Modulus were
the following, unless indicated:
______________________________________ Gauge Chart Crosshead Length
Speed Speed (cm) (cm/min) (cm/min)
______________________________________ Straight Tensile 12 20 10
Knot Tensile 5 10 10 Break Elongation 12 20 10 Young's Modulus 12
20 10 ______________________________________
The straight tensile strength is calculated by dividing the force
to break by the initial cross-sectional area of the fiber. The
elongation to break is read directly from the stress-strain curve
of the sample allotting 4-1/6% per centimeter of horizontal
displacement.
Young's Modulus is calculated from the slope of the stress-strain
curve of the sample in the linear elastic region as follows:
##EQU1## .theta. is the angle between the slope and the horizontal,
XS is the initial cross-sectional area of the fiber, SL is the
scale load, XH is the crosshead speed, CS is the chart speed, and
GL is the gage length. The SL may be selected to provide a .theta.
close to 45.degree..
The knot tensile strength of a fiber is determined in separate
experiments. The test article is tied into a surgeon's knot with
one turn of the filament around flexible tubing of 1/4 inch inside
diameter and 1/16 inch wall thickness. The surgeon's knot is a
square knot in which the free end is first passed twice, instead of
once, through the loop, and the ends drawn taut so that a single
knot is superimposed upon a compound knot. The first knot is
started with the left end over the right end and sufficient tension
is exerted to tie the knot securely.
The specimen is placed in the INSTRON tensile tester with the knot
approximately midway between the clamps. The knot tensile strength
is calculated by dividing the force required to break by the
initial cross-sectional area of the fiber.
Conversion from metric dimensions to English dimensions (i.e. psi)
is made by applying the appropriate factors.
EXAMPLE 20
The copolyester of Example 15 is made into monofilament suture
material in accordance with the following extrusion, drawing, and
annealing conditions:
EXTRUSION
The copolyester was spun at 185.degree. C. at a shear rate of 213
sec.sup.-1 using an INSTRON Capillary Rheometer with a 40 mil die
(L/D=24.1) and a ram speed of 2 cm/min. An apparent melt viscosity
of 3000 poise was observed. The fiber was taken up at 24 ft./min
after an ice water quench; the wound fiber was dried and
subsequently drawn one week later.
DRAWING
The extrudate (diameter range: 17.0 to 18.5 mils) was drawn in two
stages employing a glycerine draw bath under the conditions of
4.times. at 55.degree. C. followed by 1.5.times. at 73.degree. C.
and subsequently water-washed and dried in vacuo at room
temperature.
ANNEALING
The drawn monofilament was annealed at 77.degree. C. for 6 hours
with 5% relaxation.
The annealed monofilaments were cut to appropriate lengths, placed
in individual paper folders and heat-sealable vented foil
envelopes. The packages were subjected to 50.degree. C. and 0.1 mm
Hg pressure for 72 hours to dry and subsequently sealed under
nitrogen. Portions of the packaged fibers were sterilized by
exposure to 2.5M rads of gamma radiation from a Co.sup.60 source.
Table I, below, displays representative properties of the dried
monofilament, both before and after sterilization, and compares the
properties with a typical dried annealed drawn monofilament made
from poly(p-dioxanone) homopolymer (Control 1):
TABLE I ______________________________________ Straight Young's
Diam., Tensile .times. Elong., Mod. .times. Fiber.sup.(1) Sample
Mils 10.sup.-3, psi % 10.sup.-3, psi I.V.
______________________________________ Before Co.sup.60 Irradiation
Example 20 8.0 56.7 43 218 1.52 Control 1 7.8 70.9 39 310 1.60
After Co.sup.60 Irradiation Example 20 8.1 50.4 42 225 1.13 Control
1 8.2 58.0 37 301 1.21 ______________________________________
.sup.(1) Inherent viscosity of the fiber, tested in HFIP at
25.degree. C. and a concentration of 0.1 gm/dl.
BREAKING STRENGTH RETENTION
The breaking strength retention (BSR) of a fiber is determined by
implanting two strands of the fiber in the dorsal subcutis of each
of a number of Long-Evans rats. The number of rats used is a
function of the number of implantation periods, employing 4 rats
per period giving a total of eight (8) examples for each of the
periods. Thus 16, 24, or 32 segments of each fiber are implanted
corresponding to two, three, or four implantation periods. The
periods of in vivo residence are 7, 14, 21, or 28 days. The ratio
of the mean value of 8 determinations of the breaking strength
(determined with an INSTRON Tensile tester employing the following
settings: a gage length of 1 inch, a chart speed of 1 inch/minute,
and a crosshead speed of 1 inch/minute) at each period to the mean
value (of 8 determinations) obtained for the fiber prior to
implantation constitutes its breaking strength retention for that
period.
The results of the BSR tests for the packaged and Co.sup.60
sterilized monofilament of Example 20 are displayed in Table II,
compared with the BSR for Control 1 (also packaged and Co.sup.60
sterilized):
TABLE II ______________________________________ In Vivo Breaking
Strength Retention Diam., Initial % BSR Sample Mils Strength, lbs.
14 21 28 (days) ______________________________________ Example 20
8.1 2.61 62 55 40 Control 1 8.2 3.08 43 30 25
______________________________________
EXAMPLE 21
The copolyester of Example 14 is made into monofilament suture
material in accordance with the following extrusion, drawing, and
annealing conditions:
EXTRUSION
The copolyester was spun at 165.degree. C. at a shear rate of 213
sec.sup.-1 using an INSTRON Capillary Rheometer with a 40 mil die
(L/D=24.1) and a ram speed of 2 cm/min. An apparent melt viscosity
of 8100 poise was observed. The fiber was taken up at 24 ft/min
after an ice water quench; the wound fiber was dried and
subsequently drawn six days later.
DRAWING
The extrudate (diameter range: 19.0 to 20.0 mils) was drawn in two
stages employing a glycerine draw bath under the conditions of
4.times. at 58.degree. C. followed by 1.5.times. and 70.degree. C.
and subsequently water-washed and dried in vacuo at room
temperature.
ANNEALING
The drawn monofilament was annealed at 80.degree. C. for 6 hours
with 5% relaxation.
The annealed monofilament was cut to appropriate lengths, placed in
individual paper folders and heat-sealable vented foil envelopes.
The packages were subjected to 50.degree. C. and 0.1 mm Hg pressure
for 24 hours to dry and subsequently sealed under nitrogen.
Portions of the packaged fibers were sterilized by exposure to 2.5M
rads of gamma radiation from a Co.sup.60 source. Table III, below,
displays certain physical properties of the annealed monofilament
of Example 21 prior to drying and sterilization as well as the in
vivo breaking strength retention of the sterilized suture
material.
TABLE III ______________________________________ Diam., Tensile,
Elong., Young's mod., mils psi % psi
______________________________________ Non-Sterile 8.2 73,600 30
285,000 ______________________________________ Initial Straight
Breaking Strength, % BSR lbs. 21 28 (days)
______________________________________ Co.sup.60 sterilized 3.95 49
28 ______________________________________
EXAMPLE 22
The copolyester of Example 11 is made into monofilament suture
material in accordance with the following extrusion, drawing, and
annealing conditions:
EXTRUSION
The copolyester was spun at 175.degree. C. at a shear rate of 213
sec.sup.-1 using an INSTRON Capillary Rheometer with a 40 mil die
(L/D=24.1) and a ram speed of 2 cm/min. An apparent melt viscosity
of 3800 poise was observed. The fiber was taken up at 38.5
feet/minute after an ice water quench; the wound fiber was dried
and subsequently drawn 5 days later.
DRAWING
The extrudate (diameter range: 13.0 to 15.5 mils) was drawn in two
stages employing a glycerine draw bath under the conditions of
4.times. at 53.degree. C. followed by 1.25.times. at 72.degree. C.
and subsequently water-washed and dried in vacuo at room
temperature.
ANNEALING
The drawn monofilament was annealed at 80.degree. C. for 6 hours
with 5% relaxation.
EXAMPLE 23
The copolyester of Example 12 is made into monofilament suture
material in accordance with the following extrusion, drawing, and
annealing conditions:
EXTRUSION
The copolyester was spun at 155.degree. C. at a shear rate of 213
sec.sup.-1 using an INSTRON Capillary Rheometer with a 40 mil die
(L/D=24.1) and a ram speed of 2 cm/min. An apparent melt viscosity
of 5900 poise was observed. The fiber was taken up at 24
feet/minute after an ice water quench; the wound fiber was dried
and subsequently drawn the next day.
DRAWING
The extrudate (diameter range: 18.5 to 19.5 mils) was drawn in two
stages employing a glycerine draw bath under the conditions of
4.times. at 56.degree. C. followed by 1.5.times. at 72.degree. C.
and subsequently water-washed and dried in vacuo at room
temperature.
ANNEALING
The drawn monofilament was annealed at 80.degree. C. for 6 hours
with 5% relaxation.
EXAMPLE 24
The copolyester of Example 10 is made into monofilament suture
material in accordance with the following extrusion, drawing, and
annealing conditions:
EXTRUSION
The copolyester was spun at 170.degree. C. at a shear rate of 213
sec.sup.-1 using an INSTRON Capillary Rheometer with a 40 mil die
(L/D=24.1) and a ram speed of 2 cm/min. An apparent melt viscosity
of 8800 poise was observed. The fiber was taken up at 28
feet/minute after an ice water quench; the wound fiber was dried
and subsequently drawn the next day.
DRAWING
The extrudate (diameter range 16.0 to 18.0 mils) was drawn in two
stages employing a glycerine draw bath under the conditions of
5.times. at 61.degree. C. followed by 1.2.times. at 69.degree. C.
and subsequently water-washed and dried in vacuo at room
temperature.
ANNEALING
The drawn monofilament was annealed at 80.degree. C. for 61/4 hours
with 5% relaxation.
The annealed monofilaments of Examples 22, 23, and 24 were cut to
appropriate lengths, placed in individual paper folders and
heat-sealable vented foil envelopes. The packages were subjected to
50.degree. C. and 0.1 mm Hg pressure for 72 hours to dry and
subsequently sealed under nitrogen. Portions of the packaged fibers
were sterilized by exposure to 2.5 Mrads of gamma radiation from a
Co.sup.60 source. Representative properties of the dried annealed
monofilaments, both before and after Co.sup.60 sterilization are
displayed below in Table IV. Control 1 (also packaged and Co.sup.60
sterilized) is included for comparison purposes.
TABLE IV ______________________________________ Straight Tensile
.times. Young's Diam., 10.sup.-3, Elong., Mod. .times. 10.sup.-3,
Fiber Mils psi % psi I.V. ______________________________________
Before Co.sup.60 Irradiation Ex. 22 6.2 60.9 42 163 1.62 Ex. 23 7.8
57.0 61 175 1.53 Ex. 24 7.4 56.8 47 111 1.67 Control 1 7.8 70.9 39
310 1.60 After Co.sup.60 Irradiation Ex. 22 7.0 49.9 45 153 1.48
Ex. 23 8.0 51.9 67 174 1.38 Ex. 24 7.8 48.5 55 115 1.69 Control 1
8.2 58 37 301 1.21 ______________________________________
The in vivo breaking strength retention profiles of the sterilized
monofilaments of Examples 22, 23, and 24 were determined. The
results are displayed in Table V:
TABLE V ______________________________________ In vivo BSR Initial
Strength, BSR % Sample lbs 21 days 28 days
______________________________________ Ex. 22 1.69 61 47 Ex. 23
2.53 66 43 Ex. 24 2.34 71 57 Control 1 3.08 30 25
______________________________________
EXAMPLE 25
The copolyester of Example 16 is made into monofilament suture
material in accordance with the following extrusion, drawing, and
annealing conditions:
EXTRUSION
The copolyester was spun at 165.degree. C. at a shear rate of 213
sec.sup.-1 using an INSTRON Capillary Rheometer with a 40 mil die
(L/D=24.1) and a ram speed of 2 cm/min. An apparent melt viscosity
of 9100 poise was observed. The fiber was taken up at 24
feet/minute after an ice water quench; the wound fiber was dried
and subsequently drawn the same day.
DRAWING
The extrudate (diameter range 16.0 to 19.5 mils) was drawn in two
stages employing a glycerine draw bath under the conditions of
4.times. at 60.degree. C. followed by 1.25.times. at 80.degree. C.
and subsequently water-washed and dried in vacuo at room
temperature.
ANNEALING
The drawn monofilament was annealed at 80.degree. C. for 6 hours
with 5% relaxation.
EXAMPLE 26
The copolyester of Example 17 is made into monofilament suture
material in accordance with the following extrusion, drawing, and
annealing conditions:
EXTRUSION
The copolyester was spun at 170.degree. C. at a shear rate of 213
sec.sup.-1 using an INSTRON Capillary Rheometer with a 40 mil die
(L/D=24.1) and a ram speed of 2 cm/min. An apparent melt viscosity
of 2800 poise was observed. The fiber was taken up at 24
feet/minute after an ice water quench; the wound fiber was dried
and subsequently drawn the next day.
DRAWING The extrudate (diameter range: 17.5 to 19.5 mils) was drawn
in two stages employing a glycerine draw bath under the conditions
of 4.times. at 52.degree. C. followed by 1.5.times. at 70.degree.
C. and subsequently water-washed and dried in vacuo at room
temperature.
ANNEALING
The drawn monofilament was annealed at 80.degree. C. for 6 hours
with 5% relaxation.
The annealed monofilaments of Examples 25 and 26 were cut to
appropriate lengths, placed in individual paper folders and
heat-sealable vented foil envelopes. The packages were subjected to
50.degree. C. and 0.1 mm Hg pressure for 72 hours to dry and
subsequently sealed under nitrogen. Portions of the packaged fibers
were sterilized by exposure to 2.5M rads of gamma radiation from a
Co.sup.60 source. Properties of the packaged monofilaments, both
sterile and non-sterile, are displayed below in Table VI:
TABLE VI ______________________________________ Straight Knot
Tensile, .times. Tensile .times. Young's Diam., 10.sup.-3,
10.sup.-3, Mod., .times. Elong., Sample Mils psi psi 10.sup.-3, psi
% ______________________________________ Before Co.sup.60
Irradiation Ex. 25 8.8 61.6 43.2 186 56 Ex. 26 7.7 59.4 46.0 279 47
After Co.sup.60 Irradiation Ex. 25 8.1 62.5 53.5 160 57 Ex. 26 7.7
54.6 45.7 272 51 ______________________________________
The in vivo breaking strength retention profiles of the packaged
monofilaments of Example 25 before and after Co.sup.60
sterilization were determined. The results are displayed in Table
VII:
TABLE VII ______________________________________ In vivo BSR
Initial Strength, BSR % Sample lbs. 7 14 21 28 (days)
______________________________________ Non-Sterile 3.52 94 84 82 74
Sterile 3.12 91 79 72 57 ______________________________________
GENERATION OF ABSORPTION DATA
Under aseptic conditions, two 2-centimeter segments of a suture
sample are implanted into the left and right gluteal muscles of
female Long-Evans rats. Two rats per period are implanted for each
of the examination periods. The animals utilized in these studies
are handled and maintained in accordance with the requirements for
the Animal Laboratory Welfare Act and its 1970 Amendment. The rats
are killed at the appropriate periods by carbon dioxide
asphyxiation, then their gluteal muscles are excised and fixed in
buffered formalin. Utilizing standard histologic techniques, H and
E stained slides of the muscles and implanted sutures are prepared
for microscopic examination. Utilizing an ocular micrometer, the
approximate suture cross-sectional area is estimated in each site.
The cross-sectional area at five days is used as the reference
value for estimating percent cross-sectional area remaining at
subsequent intervals.
EXAMPLE 27
The absorption profiles of gamma radiation sterilized suture
material of Examples 20, 21, 22, 23, and 25 were determined;
results are presented in Table VIII below:
TABLE VIII ______________________________________ Median Percent
Suture Area Remaining After Intramusculer Implantation in Rats*
Days Postimplantation SAMPLE 5 91 119 150 154 180 182 210
______________________________________ EXAMPLE 100 -- -- 28 -- 1 --
0 20 EXAMPLE 100 -- -- -- 3 -- 0 0 21 EXAMPLE 100 -- -- -- 0 -- 0
-- 22 EXAMPLE 100 -- -- -- 0 -- 0 -- 23 EXAMPLE 100 100 87 0 25
______________________________________ *The data represent the
median of 7-8 cross sections in 2 rats per period per sample.
EXAMPLE 28
The copolyester of Example 18 is made into monofilament suture
material in accordance with the following extrusion, drawing, and
annealing conditions:
EXTRUSION
The copolyester was spun at 150.degree. C. at a shear rate of 213
sec.sup.-1 using an INSTRON Capillary Rheometer with a 40 mil die
(1/D=24.1) and a ram speed of 2 cm/min. An apparent melt viscosity
of 8058 poise was observed. The fiber was taken up at 24
feet/minute after an ice water quench; the wound fiber was dried
and subsequently drawn the same day.
DRAWING
The extrudate (diameter range 18.0 to 20.0 mils) was drawn in two
stages employing a glycerine draw bath under the conditions of
4.times. at 49.degree. C. followed by 1.50.times. at 78.degree. C.
and subsequently water-washed and dried in vacuo at room
temperature.
ANNEALING
The drawn monofilament was annealed at 80.degree. C. for 6 hours
with 5% relaxation.
EXAMPLE 29
The copolyester of Example 19 is made into monofilament suture
material in accordance with the following extrusion, drawing, and
annealing conditions:
EXTRUSION
The copolyester was spun at 155.degree. C. at a shear rate of 213
sec.sup.-1 using an INSTRON Capillary Rheometer with a 40 mil die
(L/D=24.1) and a ram speed of 2 cm/min. An apparent melt viscosity
of 7789 poise was observed. The fiber was taken up at 24
feet/minute after an ice water quench; the wound fiber was dried
and subsequently drawn on the 14th day.
DRAWING
The extrudate (diameter range: 20.0 to 22.0 mils) was drawn in two
stages employing a glycerine draw bath under the conditions of
5.times. at 60.degree. C. followed by 1.2.times. at 80.degree. C.
and subsequently water-washed and dried in vacuo at room
temperature.
ANNEALING
The drawn monofilament was annealed at 80.degree. C. for 6 hours
with 5% relaxation.
The annealed monofilaments of Examples 29 and 30 were cut to
appropriate lengths, placed in individual paper folders and
heat-sealable vented foil envelopes. The packages were subjected to
50.degree. C. and 0.1 mm Hg pressure for 72 hours to dry and
subsequently sealed under nitrogen. Portions of the packaged fibers
were sterilized by exposure to 2.5Mrads of gamma radiation from a
Co.sup.60 source. Properties of the packaged monofilaments, both
sterile and non-sterile, are displayed below in Table IX:
TABLE IX ______________________________________ Straight Knot
Tensile .times. Tensile .times. Young's Diam., 10.sup.-3,
10.sup.-3, Mod., .times. Elong., Sample Mils psi psi 10.sup.-3, psi
% ______________________________________ Before Co.sup.60
Irradiation Ex. 28 7.5 84.7 60.2 153 51 Ex. 29 8.2 59.3 50.9 191 60
After Co.sup.60 Irradiation Ex. 28 7.7 69.2 49.5 144 53 Ex. 29 8.0
54.0 50.0 189 55 ______________________________________
A preferred utility of the copolyesters of the invention is the
preparation of absorbable surgical filaments such as sutures and
ligatures.
This utility has been illustrated in detail above. The utility of
the surgical filaments of the invention is enhanced because said
filaments can be sterilized by gamma radiation and still retain a
useful level of physical properties, and because said filaments
have a highly desirable combination of properties. One particularly
interesting property exhibited by the subject filaments is
relatively low Young's modulus, e.g., below 300,000 psi, which is
an indication of good compliance, combined with acceptable straight
tensile strength, e.g., above 40,000 psi. For instance, see the
data presented in Table IV, above, in which filaments made from the
subject copolyesters are compared with filaments made from
p-dioxanone homopolymers. It has also been found that the
copolyesters of the invention, in the form of surgical filaments,
exhibit minimal tissue reaction after implantation in vivo. This is
a highly desirable property of a material designed to be used as an
absorbable surgical device.
While surgical filaments such as sutures and ligatures is the
preferred utility for the subject copolyesters, other surgical
devices can be fabricated from the copolyesters. Illustrative are
absorbable films, membranes, fabrics, composites, and the like.
* * * * *